Thiazole compounds and methods of making them



Patented s 25,193e a v 1: (tun-En e X EdwinL Buchmani New fork, N. v Research Corporation, New York, NET-ya corlNn-ation ofNewYork=--- v NoDrawing. Application Mar-ch18; 1935, we I Serial No. I I a 1;, 7 Claims. (crate- 3oz) This invention'relates to thiazole compounds "*isa suchasbromine, chlorine or iodine,-j

and methods of making them,- and more partlcuand R} has the same meaning as above, with a larly to thiazole compounds suitableioruse in ,thiojamide compound or the typeZCSNHa,;.in. the synthesis of the antineuritic vitamin-and w i h Z 88 h Sa mfl ce'as fl e 5 methods of making suchcompounds. react fln'w lch nla ejis bellevedtto be l I' ii In an article entitled Structure of, vitamin B" "sented by theiollowing equation: i by R. R. Williams, which was published in the j Cm g Journal'ot the Americanchemical'Society,-vol. t 1-.:: svyp ge 229 (1935);, the probable structural F"?99 9 fi- B 2 "j 10 formulae! theantineuritic vitamin, also known t t 1 t vitamin B and vitamin B1, is'disclosed. This q, vitamin is useful ,as a therapeutic agent in the treatment of certain ,disea'ses," among which is 1; a t I beriberi. It is also useful as a supplement to cercompounds the second -t m v re kndwn I I t'ain foodstuffs for the promotion of growth. and

asw-thiazolezderivatives, may'be readily Prepared well being of animals including man.- It has been b removinggthe acids g m mg o th round that this vitamin is a chemical compound mama. I

which comprises a thiazole derivative and ;a g is to be fl w h fit -i tm e pyrimidine derivative in chemical combination; compounds" as used herein in the annexed I object of the invfimtmn is 150 pmvide hifl claims, is intended to. include both the above de- 20 compounds. a d particularly ev i a scribed salts of thiazol'e derivatives and the thia- 1111 in h i e anflneuritis vitamin zole derivatives themselves. Also the term thlasimilar a zolesalts means the salts of the thiazole deriva- A further object of the invention is tov provide five mentioned above i 5 useful and effective methods of producingthiazole communds the types describedsons skilled in the-art how the invention may The present invention relates to the synthesis be, practiced, is the-condensation: bftmo' form? of thiazole derivatives or their salts which reamlderncsmfwlthlthe' c g propyl 8L semble or comprise the thiazole portion of the cohol m'vmg the formula, s

vitamin B1 and which may be intermediates suit- I j able for combining with pyrimidine groups or j/ groups capable of being converted into pyrimidine I a t, t I n 'I'hio i'ormamide is usually made by introducing gigging) d20 1 m the antineuritic vitamin or related forum m1 HCONHZ, and? p o h pent Thiazole compounds embodyingthe invention sulphide P355, 1 dry-etherrshakmg 1'. 110m have the formulae: 1 distillation. The" brom tceto' propyl alcohol, CH; t on, which may also bedesignated 3 brom 3 aceto l C: J propan 101, may be prepared in accordance with t t my processdescribed in the copending applicai l N tion,SerialN o. 11,683,1iled March 18,1935. 9

x: c 'ci In the process coveredjbythis copending apj plication, bromine is added to a water solution of v 3 aceto propan 1 01 and in the ensuing reaction 7 in which X represents an ionic halogen or an acid, 3 brom 3-aceto propan 1'; ol isprpduced. V v 45 radical, Z'is hydrogen; an amino group, a sulf- Inf this process the requisite weights oithio t. hydryl group or other group capable of-being formamide and the abovedescribed brom aceto easily converted into or replaced by hydrogen," propyl alcohol are'idissolvedfin alcohol and thefand R is the group CHzCI-hOH or ancth'er'sroun; solution'ailowed to stand, after which the product 'such as CHzCOOH, CHzCHO, QHzCQOCzHs, or: is"pu riiji ed by suitable operationsj In practice the like which" can be replaced by or converted; it has been found that satisfactoryresults may be into CHzCHzOH. Compounds oi the first typet obtained by dissolving about. 23 grams of crude which are termed salts of thiaaole derivatives, may. thio formamide and i6 igrams ioitthe liaroin aceto be prepared by condensing ahalogen ketonic a propyl alcohol in 30 cubic centimeters oi absolute A specific example; which will illustrate to per- 25 the mixture tofstandand-removing' the ether by g 4 compound of the type CHaCOCHXR, in which-X alcohol and allowing themiirture to stand 01321 68 hours at room temperature. The resulting prodis soluble in water butinsoluble in ether After the mixture has stood the requiredglength' of time, 100 cc. of water and 200cc. of 'ether are added and the material allowed to stand whereupon the mixture separates into two layers, the 1 lower layer comprising an impure water'solution of the thiazole salt and the upper layer comprising impure ether. The lower layer is separated from the ethereal layer and the thiazole salt contained therein is removed therefrom byany suit-- able operations such as are 'weli known inthe art. H a v =which corresponds'to the thiazole salt containing brominejpreviously described. The chlor aceto propyl alcohol employed in this reaction may be 7 made by direct chlorination of the aceto propyi alcohol.- The 3brom 'and 3 chlor derivatives of A satisfactory method of obtaining a pureproduct from thewater solution of the thiazole salt comprises adding an alkali, such assodium'hydroxide, to the water solution to liberatethe thiazole derivative from its combinationwith hydrobromic acid. The alkaline liquid is then repeatedly extracted with ether which extracts the free thiazole'derivative, and-the ethereal solution comprising the several extracts is dried over a dehydrating agent, such as anhydrous sodium sulphate, after which the ether is distilled off. The remaining oil is distilled in vacuo and the distillate collected. Thedistillate, a clear, viscous oil having-a faint basic-odor and boiling at 100 C. under a pressure about l mm. of mercury, is 4-methyl 5-(p-hydroxy ethyl) thiazole, .which has the graphic formula:

About 3 of this thiazole derivative are produced when the-above mentioned quantities of 'brom aceto propyl alcohol and thio formamide are employed. 'When the material is to be made in quantities, it will be obvious that larger amounts of these ingredients should be used.

This material forms addition products with acids, such as hydrohalic acids,'in"which the'acids are added'directly to the nitrogen of the thiazole added to a water solution of oneof these thiazole salts, a characteristic crystalline picrolonate resultswhich decomposes on heating to 184?- C.

The salts ofthese thiazole compounds are crystalline materials-that are usually soluble in water but insoluble in ether, and form valuable intermediate productsfor the production of the antineuritic vitamin, or similar compounds- By suitablereactions a pyrimidine derivative,

or a compound capable of being converted into such a derivative, may be caused to ailix itself to chemical combination.

the nitrogen atom in one ofthe above described thiazole compounds and thereby produce a product analogous to the antineuritic vitamin in which the 'pyrimidine and thiazole nuclei are in Although in the specific embodiment of the invention which has been described, a brom aceto ,propyl alcohol is the halogen derivative employed,

'propyl alcohol, 3 chlor 3 aceto propan 1 01, may "be caused to react with thio formamide to produce- In a =c-0Hmmon 3 aceto propan 1' 01 may also be prepared'by hydrolizing the a brom and a' chlor derivatives of-a acetobutyro-lactone. In this connection,

see Jo r. Amer. Chem. Soc., voi.5 8 p. 1803 .(l936) This invention also contemplates the production of thiazole compounds containing iodine from the corresponding halogen lretonic compound containing iodine. The 3 iodo'derivative of 3 The inventioniembraces the production of thi-' azole compounds" by condensing compounds of'the general type CI-IsCOCHXR, in which X is a halogen andR-may be the group CHzCHiOI-I. ora group which may be converted into or replaced by I Cl-izCHzOI-I, 'withfcompounds of the typ 'ZCSNI-lz, in which Z is hydrogen, anamino group, a sulfhydryl or other group which may be readily converted'into or "replaced by hydrogen, The

kind of reaction which occurs when .R is

CHzCHzOH and Z is hydrogen has already been described, By analogous reactions related compounds, in which R. represents a group, such as CHaCOOH, CHzCI-IQ, CHzCOOCzHs, ornthe' like, and Z is an amino or a sulfhydryl group, may' be prepared. Ii! desired, these compounds maybe converted into derivatives 'in. vwhich Rfl is CHzCHzOH and Z-is hydrogen by suitable reactions well known in the art. For example, the groups Cl-hCOOI-I, CHzCHO and CHgCOOCzHs, may be converted into CHzCHzOH by reduction.

An amino group may be converted into hydrogen by treatment with nitrousacid, and a sulfhydryl group may similarly be converted or replaced by the action of an oxidizing agent,such as nitric acid or hydrogen peroxide.

' It willof course be understood that other solvents and reagents may be employed to assist in carrying out the reactions and to purify the products obtained. Furthermore, it may be necessary to vary the relative proportions of the ingredientsathe timeand/or temperature of the reactions in accordance with the particular de-.

rivative which is to be produced. These variations are such as are'clearly understood by those familiar with the art.

vWhat is claimed is:- a

l. The method of making thiazole compounds which comprises condensing thio formamide with which comprises condensing} with thio formamide, and treating the resultingv compound to convert the group represented by B into CHaCHzOH.

3. The method oi making thiazole compounds, which comprises condensing 3 brom 3 aceto propan l 01 with thio iormamide.

4. The method 0! making thiazole compounds,

pan 1 01 with thio formamide. l

5. The method of making thiazole compounds which comprises condensing a compound having, the formula CHaCOCHXCHaCHzOH, in which X chlor 3 aceto prorepresents a halogen of the group consisting of bromine, iodine and chlorine, with thio tormnmide.

6. The method oi. making thiazole compounds which comprises condensing a. compound having the formula CHaCOCI-IXCHzCI-IzOH, in which X represents a. halogen of the group consisting of iodine, bromine or chlorine, with thio Iormamide and treating the resulting product with an alkali.

7. The method of making thinzole compounds which comprises condensing 3 iodo 3' aceto propen 1 01 with thio tormamide.

nnwm a. poem. 

